We are in the midst of the resistance era for antibiotics, not quite a century after penicillin was discovered in 1929. Drugs meant to fight infections are fighting hard to even make it out of the lab and into the market—without much avail.

McMaster University researchers Eric Brown and Gerard Wright’s paper “Antibacterial drug discovery in the resistance era” published in Nature January 20, paints the picture we currently find ourselves in, the path we took to get here, and offers glimpses into the future of infection-fighting medicine.

The golden age of treating disease with antibiotics (including penicillin and the 1943 discovery of streptomycin) favoured natural products that are the source of most antibiotic medicine. But as they are chemically complex and difficult to derivatize, their use has fallen out of favour with most large pharmaceutical companies.

This golden age was followed by the medicinal chemistry era from the ‘60s to ‘90s when a transformation in medicine took place. Most pharmaceutical companies use the synthetic chemicals created during this time rather than the natural products of before, but their efficacy is at risk as the broad use of antibiotics in humans, animals and agriculture has created a great resistance among bacterial populations.

There are advantages and disadvantages stemming from both eras of research, but as Brown and Wright point out, “the overall result is a stalemate in discovery: screens of natural-product libraries identify bioactive but known compounds, and screens of synthetic libraries identify potent ligands of biochemical targets but with poor bioactivity.”

One solution they offer is the “development of synthetic libraries that capture the chemical diversity and physicochemical properties of natural products.” And another is to “capitalize on the ability of synthetic compounds to inhibit essential bacterial targets by developing delivery systems that solve the cell-envelope penetration and efflux challenges.”

In fact, known chemical scaffolds of natural products that have long been abandoned are being revisited in the hopes of finding a way to conquer bacterial resistance.

For the past two decades, the genes-to-drugs model has been in use, but despite advances in medicinal technology and computing, it has not led to the discovery of any new medicines. Brown and Wright point out that diseases that were once easily treatable have become deadly again. This fact, coupled with limited antibacterial drug discovery, has many, from scientists to the general public, accepting that we are in a crisis.

The authors are hopeful that looking to the history of antibiotic discovery, combined with a “fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that will be able to control infection in the resistance era.” But they do not deny that it will be challenging to develop new antibiotic drugs as the modern era of research has shown that “antibiotics that are highly effective, safe and broad spectrum are incredibly difficult to find.”